I. What every physician needs to know.

Endometrial cancer appears to have two forms: the first, or Type I, is linked to estrogen stimulation and comprises 80% of the cases. The second, or type 2 (comprising the remaining 20%), does not appear to have any linkage to estrogen stimulation and therefore does not have the typical associations as type I patients. Endometrial cancer is usually caught as early stage disease due to its early symptomatology. Endometrial cancer is a surgical disease, and unlike cervical cancer, even those with locally advanced malignancies confined to the pelvis often benefit from surgical resection.

Transvaginal ultrasound showing thickened endometrial stripe is supportive of the diagnosis, with thickness approaching or exceeding 20mm being highly suggestive of malignancy, and less than 4mm being supportive of benign causes. Only direct histologic sampling such as with an endometrial biopsy establishes the diagnosis.

Endometrial biopsy is the best test to exclude endometrial cancer, and those with persistent bleeding despite a normal or thin endometrial stripe should undergo this office procedure. Those patients with thin endometrial stripes and persistent bleeding should also be considered for biopsy.

A. History Part I: Pattern Recognition:

The typical woman with endometrial cancer presents with post-menopausal vaginal bleeding. The amount or frequency of bleeding is not important as any bleeding in a post menopausal woman should prompt thorough evaluation. Five to 20% of women with post-menopausal bleeding will be found to have endometrial cancer, with the likelihood increasing as the years beyond menopause increase. However, all women with postmenopausal bleeding should be considered to have endometrial cancer until proven otherwise.

B. History Part 2: Prevalence:

Endometrial cancer is the most common gynecologic malignancy in the United States, and affects over 40,000 women yearly. This makes the lifetime risk of endometrial cancer for women 3%. However, women with Lynch Syndrome (hereditary nonpolyposis coli) have lifetime risks estimated at 27-71%.

In Type I (estrogen stimulated) endometrial cancer, the common associations are with elevated estrogen: exogenous, or endogenous. Exogenous sources of estrogenic stimulation includes hormone supplementation, especially when unopposed by a progestin, or tamoxifen therapy. It is estimated that hormone replacement with unopposed estrogen elevates the relative risk to somewhere between 3-15%, depending on the dose of estrogens and duration of therapy. Arguably, the most common source of increased endogenous estrogen is obesity. Adipose cells convert adrenal presursors to estradiol and estrone. Women with chronic elevation of estrogen due to chronic anovulation (such as with Polycystic Ovarian Syndrome) are also at risk of endometrial hyperplasia and subsequent malignancy.

Endometrial cancer should be suspected in younger women with PCOS and abnormal uterine bleeding. Higher body mass index is also associated with development of this disease in ages less than 45, and is also associated with a higher risk of death, perhaps due to stimulation of metastatic foci's growth by estrogen. However, women with very high BMI's (>40) are more likely to present with stage I disease than those with BMI's of 30, and are more likely to have the more favorable endometroid histology.

C. History Part 3: Competing diagnoses that can mimic Endometrial Cancer.

Cervical cancer can also mimic endometrial cancer as it can cause post menopausal bleeding. The other causes of postmenopausal bleeding are vaginal or endometrial uterine atrophy, which would typically show an endometrial stripe of less then <4mm on transvaginal ultrasound. Hormonal effect, choriocarcinoma, leiomyomata uteri (fibroids), ruptured sigmoid diverticulum with fistulization, polyps, endometrial hyperplasia, anticoagulants, endometritis, or even lymphoma have also been implicated.

D. Physical Examination Findings.

Bilateral lower extremity edema, often accompanied by back pain, is a dismal finding that suggests bulky para-aortic lymphadenopathy with compression of the inferior vena cava. Vaginal exam and cervical exam are normal except in advanced disease. Bimanual palpation may reveal an enlarged uterus with more advanced cases, although this can be difficult to discern given the disease's predilection for obese women. Ascites signifies advanced disease.

E. What diagnostic tests should be performed?

Ultrasound to assess thickness of the endometrial stripe is useful as an initial step, and endometrial biopsy yields the diagnosis and is relatively non invasive (office procedure). Pap smear should also be performed, as if the patient has a coexistent cervical cancer, the patient will need a radical hysterectomy rather than total abdominal hysterectomy. Dilation and curretage can also be used, however, it is more expensive and more invasive than endometrial biopsy.

Pre-surgical imaging test aside from a chest radiograph are not necessary for the purposes of staging, as patients with endometrial cancer will be staged surgically. However, in patients with clinically advanced disease by physical examination, computed tomography (CT) scan of the abdomen of pelvis may be useful in planning surgery or judging resectability. Those who are medically inoperable should undergo contrast enhanced magnetic resonance imaging (MRI) to judge presence of cervical involvement as well as lymph node metastasis, as this will help radiotherapy planning and delivery.

Although peritoneal cytology was widely used historically in this disease, it has been removed from staging in the most recent edition as patients with positive peritoneal washings did not seem to have an adverse prognosis.

1. What laboratory studies should be ordered to help establish the diagnosis? How should the results be interpreted?

Serum tests are not diagnostic, and biopsy is the gold standard.

2. What imaging studies should be ordered to help establish the diagnosis? How should the results be interpreted?

Transvaginal ultrasound showing thickened endometrial stripe is supportive of the diagnosis, with thickness approaching or exceeding 20mm being highly suggestive of malignancy. CT is not sensitive for this disease, and PET scanning is not routinely used.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

CA 125 levels of >40 have an 80% specificity for lymph node metastases, but this test does not establish the diagnosis.

III. Default Management.

Acute, hemodynamically significant bleeding should be managed with fluid resuscitation and transfusion. Vaginal packing may be helpful to decrease bleeding, particularly if there is cervical extension and the bleeding seems to be coming from a cervical source (as packing is able to then directly compress the source of bleeding). Uterine artery embolization may be required in order to stop significant bleeding.

A. Immediate management.

Fluid resuscitation should be performed in those with signs of hemodynamic instability.

B. Physical Examination Tips to Guide Management.

Pelvic and rectal exam is helpful to exclude vaginal, rectal, or cervical source for the bleeding.

A complete blood count to assess hemoglobin response to transfusions, if necessary.

CA-125, if initially elevated, can be useful in following patients for recurrence.

D. Long-term management.

Optimal management of early stage endometrial cancer is total abdominal hysterectomy and bilateral salpingo-oophorectomy. Radical hysterectomy, which involves resection of the vagina with the uterus en bloc, is rarely required.

In women with intermediate risk disease, there is a subpopulation of high intermediate risk patients which includes women with all three of the following: lymphovascular invasion, outer one third myometrial invasion, grade 2 or 3 differentiation; patients aged 50-69 years of age with 2 of the aforementioned risk factors, or patients who are 70 or older and have one or more of the aforementioned risk factors.

Patients considered high risk have gross involvement of the cervix, papillary serous or clear cell histology, or stage III or IV disease (i.e. involvement of uterine serosa or adnexa, presence of metastasis). Stage III or IV patients may benefit from chemotherapy.

E. Common Pitfalls and Side-Effects of Management.

Gynecologic oncologists, where available, are preferred for definitive management due to their increased ability as a group to provide detailed surgical staging. Endometrial biopsy should precede total abdominal hysterectomy in the setting of postmenopausal bleeding so a second procedure does not need to occur for surgical staging.

IV. Management with Co-Morbidities.

Women with inoperable clinical Stage I endometrial cancer can be treated for cure with radiotherapy. In fact, for many years endometrial cancer was a radiotherapeutic disease, not a surgical one. However, the definitive procedure involves an intraoperative implant, which will require spinal anesthesia for proper placement in nearly all instances. Published data suggests that results are equivalent in those with poor surgical candidacy, and about a third of deaths in these patients were due to intercurrent disease.

Medically inoperable patients with limited life span (or young patients with early disease desirous of fertility) can also be managed with megestrol acetate (megace) - a 76% response rate, and a median time to progression of 19 months.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Patients actively bleeding should have serial hemoglobins.

B. Anticipated Length of Stay.

Acute bleeding episodes should require length of stays between 3-7 days, depending on the rapidity with which the bleeding can be controlled.

C. When is the Patient Ready for Discharge.

Hemoglobins should be stabilized and there should be minimal (<1-2 pads/day) vaginal bleeding.

D. Arranging for Clinic Follow-up.

Patients should have follow up with a gynecologic oncologist to plan surgical resection.

1. When should clinic follow up be arranged and with whom.

Patients should have follow up with a gynecologic oncologist to plan surgical resection.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

Endometrial biopsy should be obtained where possible so that results are available as an outpatient.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Hemoglobin should be checked prior to a clinic visit if a patient persists in bleeding.

E. Placement Considerations.

None

F. Prognosis and Patient Counseling.

Stage I endometrial cancer (confined to uterus) has an overall survival of 80-90% at 5 years. Stage II (invades cervix but remains confined to uterus) is 75%, stage III (involves serosa or adnexa) is approximately 50%, and Stage IV (involves bladder or bowel, or distant metastases) is 20%.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

There are no JCAHO Core indicators that are referable to this disease.